The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. ...The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. Recently, the aberrant and deranged signaling of the cGAS-STING axis is closely implicated in multiple sterile inflammatory diseases, including heart failure,myocardial infarction, cardiac hypertrophy, nonalcoholic fatty liver diseases, aortic aneurysm and dissection, obesity, etc. This is because of the massive loads of damage-associated molecular patterns(mitochondrial DNA, DNA in extracellular vesicles) liberated from recurrent injury to metabolic cellular organelles and tissues, which are sensed by the pathway. Also, the cGAS-STING pathway crosstalk with essential intracellular homeostasis processes like apoptosis, autophagy, and regulate cellular metabolism.Targeting derailed STING signaling has become necessary for chronic inflammatory diseases. Meanwhile, excessive type I interferons signaling impact on cardiovascular and metabolic health remain entirely elusive. In this review, we summarize the intimate connection between the cGAS-STING pathway and cardiovascular and metabolic disorders. We also discuss some potential small molecule inhibitors for the pathway. This review provides insight to stimulate interest in and support future research into understanding this signaling axis in cardiovascular and metabolic tissues and diseases.展开更多
Multiple cancer immunotherapies including chimeric antigen receptor T cell and immune checkpoint inhibitors(ICIs)have been successfully developed to treat various cancers by motivating the adaptive anti-tumor immunity...Multiple cancer immunotherapies including chimeric antigen receptor T cell and immune checkpoint inhibitors(ICIs)have been successfully developed to treat various cancers by motivating the adaptive anti-tumor immunity.Particularly,the checkpoint blockade approach has achieved great clinic success as evidenced by several U.S.Food and Drug Administration(FDA)-approved antiprogrammed death receptor 1/ligand 1 or anti-cytotoxic T lymphocyte associated protein 4 antibodies.However,the majority of cancers have low clinical response rates to these ICIs due to poor tumor immunogenicity.Indeed,the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes-TANK-binding kinase 1(cGAS-STING-TBK1)axis is now appreciated as the major signaling pathway in innate immune response across different species.Aberrant signaling of this pathway has been closely linked to multiple diseases,including auto-inflammation,virus infection and cancers.In this perspective,we provide an updated review on the latest progress on the development of small molecule modulators targeting the cGAS-STING-TBK1 signaling pathway and their preclinical and clinical use as a new immune stimulatory therapy.Meanwhile,highlights on the clinical candidates,limitations and challenges,as well as future directions in this field are also discussed.Further,small molecule inhibitors targeting this signaling axis and their potential therapeutic use for various indications are discussed as well.展开更多
Microbial components and the endogenous molecules released from damaged cells can stimulate germ-line-encoded pattern recognition receptors(PRRs)to transduce signals to the hub of the innate immune signaling network-t...Microbial components and the endogenous molecules released from damaged cells can stimulate germ-line-encoded pattern recognition receptors(PRRs)to transduce signals to the hub of the innate immune signaling network-the adaptor proteins MyD88/TRIF/MAVS/STING/Caspase-1,where integrated signals relay to the relevant transcription factors IRF3/IRF7/NF-κB/AP-1 and the signal transducer and activator of tran-scription 6(STAT6)to trigger the expression of typeІinterferons and inflammatory cytokines or the assem-bly of inflammasomes.Most pleiotropic cytokines are secreted and bind to specific receptors,activating the signaling pathways including JAK-STAT for the prolif-eration,differentiation and functional capacity of im-mune cells.This review focuses on several critical adaptors in innate immune signaling cascades and recent progress in their molecular mechanisms.展开更多
SIRT7,a sirtuin family member implicated in aging and disease,is a regulator of metabolism and stress responses.It remains elusive how human somatic stem cell populations might be impacted by SIRT7.Here,we found that ...SIRT7,a sirtuin family member implicated in aging and disease,is a regulator of metabolism and stress responses.It remains elusive how human somatic stem cell populations might be impacted by SIRT7.Here,we found that SIRT7 expression declines during human mesenchymal stem cell(hMSC)aging and that SIRT7 deficiency accelerates senescence.Mechanistically,SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins,thus maintaining the repressive state of heterochromatin at nuclear periphery.Accordingly,deficiency of SIRT7 results in loss of heterochromatin,derepression of the LINE1 retrotransposon(LINE1),and activation of innate immune signaling via the cGAS-STING pathway.These agingassociated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor.Together,these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.展开更多
Genomic instability remains an enabling feature of cancer and promotes malignant transformation.Alterations of DNA damage response(DDR)pathways allow genomic instability,generate neoantigens,upregulate the expression ...Genomic instability remains an enabling feature of cancer and promotes malignant transformation.Alterations of DNA damage response(DDR)pathways allow genomic instability,generate neoantigens,upregulate the expression of programmed death ligand 1(PD-L1)and interact with signaling such as cyclic GMPe AMP synthase-stimulator of interferon genes(cGASe STING)signaling.Here,we review the basic knowledge of DDR pathways,mechanisms of genomic instability induced by DDR alterations,impacts of DDR alterations on immune system,and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.展开更多
Autophagy plays important roles in modulating viral replication and antiviral immune response. Coronavirus infection is associated with the autophagic process, however, little is known about the mechanisms of autophag...Autophagy plays important roles in modulating viral replication and antiviral immune response. Coronavirus infection is associated with the autophagic process, however, little is known about the mechanisms of autophagy induction and its contribution to coronavirus regulation of host innate responses. Here, we show that the membrane-associated papain-like protease PLP2 （PLP2-TM） of coronaviruses acts as a novel autophagy- inducing protein. Intriguingly, PLP2-TM induces incom- plete autophagy process by increasing the accumula- tion of autophagosomes but blocking the fusion of autophagosomes with lysosomes. Furthermore, PLP2- TM interacts with the key autophagy regulators, LC3 and Beclinl, and promotes Beclinl interaction with STING, the key regulator for antiviral IFN signaling. Finally, knockdown of Beclinl partially reverses PLP2-TM＇s inhibitory effect on innate immunity which resulting in decreased coronavirus replication. These results sug- gested that coronavirus papain-like protease induces incomplete autophagy by interacting with Beclinl, which in turn modulates coronavirus replication and antiviral innate immunity.展开更多
Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and con. sidered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to...Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and con. sidered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to that of its bacterial ancestor＇s, consists of a circular loop and contains significant number of unmethylated DNA as CpG islands. The innate immune system plays an important role in the mammalian immune response. Recent research has demonstrated that mitochondrial DNA （mtDNA） activates several innate immune path- ways involving TLR9, NLRP3 and STING signaling, which contributes to the signaling platforms and results in effector responses. In addition to facilitating antibac- terial immunity and regulating antiviral signaling, mounting evidence suggests that mtDNA contributes to inflammatory diseases following cellular damage and stress. Therefore, in addition to its well-appreciated roles in cellular metabolism and energy production, mtDNA appears to function as a key member in the innate immune system. Here, we highlight the emerging roles of mtDNA in innate immunity.展开更多
STING(stimulator of interferon genes)是天然免疫信号通路中一种新发现的蛋白质,在防御病毒及胞内细菌感染、介导Ⅰ型IFN产生过程中发挥重要功能.来自病原体的B型DNA与5′-3p dsRNA暴露在宿主细胞中后被相应的模式识别受体识别,通过...STING(stimulator of interferon genes)是天然免疫信号通路中一种新发现的蛋白质,在防御病毒及胞内细菌感染、介导Ⅰ型IFN产生过程中发挥重要功能.来自病原体的B型DNA与5′-3p dsRNA暴露在宿主细胞中后被相应的模式识别受体识别,通过不同的通路传递信号给STING.STING随后通过相似的机制招募TBK1激活IRF3,诱导干扰素表达.对细菌中的环二核苷酸c-di-GMP和c-di-AMP,STING则可以直接作为模式识别受体引发Ⅰ型干扰素反应.此外STING还能激活STAT6诱导特异趋化因子产生,吸引各种免疫细胞抵抗病毒感染.本文通过对STING的发现、结构、定位、功能、机理以及调节机制进行综述,以期为揭示病毒逃逸天然免疫调节机制和抗病毒新型免疫调节剂提供新的思路.展开更多
In wind tunnels, long cantilever sting support systems with low structural damping encounter flow separation and turbulence during wind tunnel tests, which results in destructive low-frequency and big-amplitude resona...In wind tunnels, long cantilever sting support systems with low structural damping encounter flow separation and turbulence during wind tunnel tests, which results in destructive low-frequency and big-amplitude resonance, leading to data quality degradation and test envelope limitation. To ensure planed test envelope and obtain high-quality data, an active damping vibration control system independent of balance signal based on stackable piezoelectric actuators and velocity feedback using accelerometer, is proposed to improve the support stability and wind tunnel testing safety in transonic wind tunnel. Meanwhile, a design of powerful sting-root embedded active damping device is given and an active vibration control method is presented based on the mechanism analysis of aircraft model vibration. Furthermore, a self-adaptive fuzzy Proportion Differentiation(PD) control model is proposed to realize control parameters adjustment automatically for various testing conditions. Besides, verification tests are performed in laboratory and a continuous transonic wind tunnel. Experimental results indicate that the aircraft model does not vibrate obviously from -4° to 11° at Ma = 0.6, the number of useable angle-of-attack has increased by 7° at Ma = 0.6 and 5° at Ma = 0.7 respectively, satisfying the requirements of practical wind tunnel tests.展开更多
The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway,comprised of cyclic GMP-AMP synthase(cGAS),stimulator of interferon genes(STING)...The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway,comprised of cyclic GMP-AMP synthase(cGAS),stimulator of interferon genes(STING), and downstream signaling adaptors, plays an essential role in protective immune defense against microbial DNA and internal damaged-associated DNA and is responsible for various immune-related diseases.After binding with DNA, cytosolic cGAS undergoes conformational change and DNA-linked liquid-liquid phase separation to produce 2’3’-c GAMP for the activation of endoplasmic reticulum(ER)-localized STING. However, further studies revealed that cGAS is predominantly expressed in the nucleus and strictly tethered to chromatin to prevent binding with nuclear DNA, and functions differently from cytosoliclocalized cGAS. Detailed delineation of this pathway,including its structure, signaling, and regulatory mechanisms, is of great significance to fully understand the diversity of cGAS-STING activation and signaling and will be of benefit for the treatment of inflammatory diseases and cancer. Here, we review recent progress on the above-mentioned perspectives of the cGAS-STING signaling pathway and discuss new avenues for further study.展开更多
We reported a case of multiple organ dysfunction syndrome （MODS） following about 300 wasp stings. The diagnosis was based on autopsy findings of acute pulmonary edema, acute kidney injury, hepatic and cardiac dysfun...We reported a case of multiple organ dysfunction syndrome （MODS） following about 300 wasp stings. The diagnosis was based on autopsy findings of acute pulmonary edema, acute kidney injury, hepatic and cardiac dysfunction, and cerebral edema. MODS is a life-threatening complication, and should be considered a possibility after multiple wasp stings. Our autopsy helped to establish the cause of unexpected death due to wasp stings and to elucidate a possible mechanism of MODS.展开更多
Immunometabolism,which is the metabolic reprogramming of anaerobic glycolysis,oxidative phosphorylation,and metabolite synthesis upon immune cell activation,has gained importance as a regulator of the homeostasis,acti...Immunometabolism,which is the metabolic reprogramming of anaerobic glycolysis,oxidative phosphorylation,and metabolite synthesis upon immune cell activation,has gained importance as a regulator of the homeostasis,activation,proliferation,and differentiation of innate and adaptive immune cell subsets that function as key factors in immunity.Metabolic changes in epithelial and other stromal cells in response to different stimulatory signals are also crucial in infection,inflammation,cancer,autoimmune diseases,and metabolic disorders.The crosstalk between the PI3K-AKT-mTOR and LKB1-AMPK signaling pathways is critical for modulating both immune and nonimmune cell metabolism.The bidirectional interaction between immune cells and metabolism is a topic of intense study.Toll-like receptors(TLRs),cytokine receptors,and T and B cell receptors have been shown to activate multiple downstream metabolic pathways.However,how intracellular innate immune sensors/receptors intersect with metabolic pathways is less well understood.The goal of this review is to examine the link between immunometabolism and the functions of several intracellular innate immune sensors or receptors,such as nucleotide-binding and leucine-rich repeat-containing receptors(NLRs,or NOD-like receptors),absent in melanoma 2(AIM2)-like receptors(ALRs),and the cyclic dinucleotide receptor stimulator of interferon genes(STING).We will focus on recent advances and describe the impact of these intracellular innate immune receptors on multiple metabolic pathways.Whenever appropriate,this review will provide a brief contextual connection to pathogenic infections,autoimmune diseases,cancers,metabolic disorders,and/or inflammatory bowel diseases.展开更多
The covalently closed circular DNA(cccDNA)of HBV plays a crucial role in viral persistence and is also a risk factor for developing HBV-induced diseases,including liver fibrosis.Stimulator of interferon genes(STING),a...The covalently closed circular DNA(cccDNA)of HBV plays a crucial role in viral persistence and is also a risk factor for developing HBV-induced diseases,including liver fibrosis.Stimulator of interferon genes(STING),a master regulator of DNA-mediated innate immune activation,is a potential therapeutic target for viral infection and virus-related diseases.In this study,agonist-induced STING signaling activation in macrophages was revealed to inhibit cccDNA-mediated transcription and HBV replication via epigenetic modification in hepatocytes.Notably,STING activation could efficiently attenuate the severity of liver injury and fibrosis in a chronic recombinant cccDNA(rcccDNA)mouse model,which is a proven suitable research platform for HBV-induced fibrosis.Mechanistically,STING-activated autophagic flux could suppress macrophage inflammasome activation,leading to the amelioration of liver injury and HBV-induced fibrosis.Overall,the activation of STING signaling could inhibit HBV replication through epigenetic suppression of cccDNA and alleviate HBV-induced liver fibrosis through the suppression of macrophage inflammasome activation by activating autophagic flux in a chronic HBV mouse model.This study suggests that targeting the STING signaling pathway may be an important therapeutic strategy to protect against persistent HBV replication and HBV-induced fibrosis.展开更多
Cellular sensing of virus-derived nucleic acids is essential for early defenses against virus infections. In recent years, the discovery of DNA sensing proteins, including cyclic GMP-AMP synthase （cGAS） and gamma-in...Cellular sensing of virus-derived nucleic acids is essential for early defenses against virus infections. In recent years, the discovery of DNA sensing proteins, including cyclic GMP-AMP synthase （cGAS） and gamma-interferon- inducible protein （IFI16）, has led to understanding of how cells evoke strong innate immune responses against incoming pathogens carrying DNA genomes. The signaling stimulated by DNA sensors depends on the adaptor protein STING （stimulator of interferon genes）, to enable expression of antiviral proteins, including type I interferon. To facilitate efficient infections, viruses have evolved a wide range of evasion strategies, targeting host DNA sensors, adaptor proteins and transcription factors. In this review, the current literature on virus-induced activation of the STING pathway is presented and we discuss recently identified viral evasion mechanisms targeting different steps in this antiviral pathway.展开更多
A modern transonic computational fluid dynamics test case is described in this paper,which is the Aerodynamic Validation Model（AVM） from the Chinese Aeronautical Establishment（CAE）. The CAE-AVM is a representation...A modern transonic computational fluid dynamics test case is described in this paper,which is the Aerodynamic Validation Model（AVM） from the Chinese Aeronautical Establishment（CAE）. The CAE-AVM is a representation of a modern transonic business jet aircraft with a design Mach number of 0.85. Numerical simulations for the AVM are conducted for two geometries： one baseline geometry, and one geometry that includes the applied model support system of the wind tunnel as well as the deformed wing shape that occurred during wind tunnel testing. The combined influence of wing deformation and model support interference on local and integral aerodynamic features is presented. Comparisons between CFD and experimental results are made; reasons of discrepancy between results from considered cases are analyzed.展开更多
Exposure to ionizing radiation,a physical treatment that inactivates live tumor cells,has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human c...Exposure to ionizing radiation,a physical treatment that inactivates live tumor cells,has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human clinical trials.However,the mechanisms by which irradiated cells function as immunogenic tumor vaccines and induce effective antitumor responses have not been fully explored.Here,we demonstrate that oxidized mitochondrial DNA(mtDNA)and stimulator of interferon genes(STING)signaling play a key roles in the enhanced antitumor effect achieved with an irradiated tumor cell vaccine.Elevations in ROS and oxidized mtDNA 8-OHG content could be induced in irradiated tumor cells.Oxidized mtDNA derived from irradiated tumor cells gained access to the cytosol of dendritic cells(DCs).Oxidized mtDNA,as a DAMP or adjuvant,activated the STING-TBK1-IRF3-IFN-β pathway in DCs,which subsequently cross-presented irradiated tumor cell-derived antigens to CD8^(+)T cells and elicited antitumor immunity.The results of our study provide insight into the mechanism by which an irradiated cell vaccine mediates antitumor immunity,which may have implications for new strategies to improve the efficacy of irradiated vaccines.展开更多
Colorectal cancer(CRC), a malignant tumor worldwide consists of microsatellite instability(MSI) and stable(MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosupp...Colorectal cancer(CRC), a malignant tumor worldwide consists of microsatellite instability(MSI) and stable(MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing wasperformed to explore the role of SHP2 in all cell types of tumor microenvironment(TME) from murine MC38 xenografts. Intratumoral cells were found to be functionally heterogeneous and responded significantly to SHP099, a SHP2 allosteric inhibitor. The malignant evolution of tumor cells was remarkably arrested by SHP099. Mechanistically, STING-TBK1-IRF3-mediated type I interferon signaling was highly activated by SHP099 in infiltrated myeloid cells. Notably, CRC patients with MSS phenotype exhibited greater macrophage infiltration and more potent SHP2 phosphorylation in CD68;macrophages than MSI-high phenotypes, suggesting the potential role of macrophagic SHP2 in TME. Collectively,our data reveals a mechanism of innate immunosuppression mediated by SHP2, suggesting that SHP2 is a promising target for colon cancer immunotherapy.展开更多
基金supported by National Key R&D Program of China(2018YFC1704500)the National Program for NSFC(81973624,81873192,81830112,China)+2 种基金the Natural Science Foundation of Tianjin City(19JCYBJC28200,China)Important Drug Develop of MOST(2019ZX09201005-002-007,China)Science and Technology Program of Tianjin(No.20ZYJDJC00070,China)。
文摘The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. Recently, the aberrant and deranged signaling of the cGAS-STING axis is closely implicated in multiple sterile inflammatory diseases, including heart failure,myocardial infarction, cardiac hypertrophy, nonalcoholic fatty liver diseases, aortic aneurysm and dissection, obesity, etc. This is because of the massive loads of damage-associated molecular patterns(mitochondrial DNA, DNA in extracellular vesicles) liberated from recurrent injury to metabolic cellular organelles and tissues, which are sensed by the pathway. Also, the cGAS-STING pathway crosstalk with essential intracellular homeostasis processes like apoptosis, autophagy, and regulate cellular metabolism.Targeting derailed STING signaling has become necessary for chronic inflammatory diseases. Meanwhile, excessive type I interferons signaling impact on cardiovascular and metabolic health remain entirely elusive. In this review, we summarize the intimate connection between the cGAS-STING pathway and cardiovascular and metabolic disorders. We also discuss some potential small molecule inhibitors for the pathway. This review provides insight to stimulate interest in and support future research into understanding this signaling axis in cardiovascular and metabolic tissues and diseases.
基金supported by grants from Natural Science Foundation of China(Nos.81773565,21877120,81703327,81430080,81573452,and 81773767,China)Supporting grants from the Key Program of the Frontier Science of the Chinese Academy of Sciences(No.160621,China)+1 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDA12020374,China)a start-up grant to the Research Laboratory of Medicinal Chemical Biology&Frontiers on Drug Discovery from Shanghai Jiao Tong University(China)are also appreciated
文摘Multiple cancer immunotherapies including chimeric antigen receptor T cell and immune checkpoint inhibitors(ICIs)have been successfully developed to treat various cancers by motivating the adaptive anti-tumor immunity.Particularly,the checkpoint blockade approach has achieved great clinic success as evidenced by several U.S.Food and Drug Administration(FDA)-approved antiprogrammed death receptor 1/ligand 1 or anti-cytotoxic T lymphocyte associated protein 4 antibodies.However,the majority of cancers have low clinical response rates to these ICIs due to poor tumor immunogenicity.Indeed,the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes-TANK-binding kinase 1(cGAS-STING-TBK1)axis is now appreciated as the major signaling pathway in innate immune response across different species.Aberrant signaling of this pathway has been closely linked to multiple diseases,including auto-inflammation,virus infection and cancers.In this perspective,we provide an updated review on the latest progress on the development of small molecule modulators targeting the cGAS-STING-TBK1 signaling pathway and their preclinical and clinical use as a new immune stimulatory therapy.Meanwhile,highlights on the clinical candidates,limitations and challenges,as well as future directions in this field are also discussed.Further,small molecule inhibitors targeting this signaling axis and their potential therapeutic use for various indications are discussed as well.
文摘Microbial components and the endogenous molecules released from damaged cells can stimulate germ-line-encoded pattern recognition receptors(PRRs)to transduce signals to the hub of the innate immune signaling network-the adaptor proteins MyD88/TRIF/MAVS/STING/Caspase-1,where integrated signals relay to the relevant transcription factors IRF3/IRF7/NF-κB/AP-1 and the signal transducer and activator of tran-scription 6(STAT6)to trigger the expression of typeІinterferons and inflammatory cytokines or the assem-bly of inflammasomes.Most pleiotropic cytokines are secreted and bind to specific receptors,activating the signaling pathways including JAK-STAT for the prolif-eration,differentiation and functional capacity of im-mune cells.This review focuses on several critical adaptors in innate immune signaling cascades and recent progress in their molecular mechanisms.
文摘SIRT7,a sirtuin family member implicated in aging and disease,is a regulator of metabolism and stress responses.It remains elusive how human somatic stem cell populations might be impacted by SIRT7.Here,we found that SIRT7 expression declines during human mesenchymal stem cell(hMSC)aging and that SIRT7 deficiency accelerates senescence.Mechanistically,SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins,thus maintaining the repressive state of heterochromatin at nuclear periphery.Accordingly,deficiency of SIRT7 results in loss of heterochromatin,derepression of the LINE1 retrotransposon(LINE1),and activation of innate immune signaling via the cGAS-STING pathway.These agingassociated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor.Together,these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.
基金supported in part by a grant from National Natural Science Foundation of China(81802255)Shanghai Pujiang Program(17PJD036,China)+6 种基金a grant from Shanghai Municipal Commission of Health and Family Planning Program(20174Y0131,China)National Key Research&Development Project(2016YFC0902300,China)major disease clinical skills enhancement program of three year action plan for promoting clinical skills and clinical innovation in municipal hospitalsShanghai Shen Kang Hospital Development Center Clinical Research Plan of SHDC(16CR1001A,China)“Dream Tutor”Outstanding Young Talents Program(fkyq1901,China)key disciplines of Shanghai Pulmonary Hospital(2017ZZ02012,China)grant of Shanghai Science and Technology Commission(16JC1405900,China)。
文摘Genomic instability remains an enabling feature of cancer and promotes malignant transformation.Alterations of DNA damage response(DDR)pathways allow genomic instability,generate neoantigens,upregulate the expression of programmed death ligand 1(PD-L1)and interact with signaling such as cyclic GMPe AMP synthase-stimulator of interferon genes(cGASe STING)signaling.Here,we review the basic knowledge of DDR pathways,mechanisms of genomic instability induced by DDR alterations,impacts of DDR alterations on immune system,and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.
基金This research was supported by grants from the National Natural Science Foundation of China （Grant Nos. 81273231,81172799 to Z. C. and 81102478, 81471947 to Y. X.）.
文摘Autophagy plays important roles in modulating viral replication and antiviral immune response. Coronavirus infection is associated with the autophagic process, however, little is known about the mechanisms of autophagy induction and its contribution to coronavirus regulation of host innate responses. Here, we show that the membrane-associated papain-like protease PLP2 （PLP2-TM） of coronaviruses acts as a novel autophagy- inducing protein. Intriguingly, PLP2-TM induces incom- plete autophagy process by increasing the accumula- tion of autophagosomes but blocking the fusion of autophagosomes with lysosomes. Furthermore, PLP2- TM interacts with the key autophagy regulators, LC3 and Beclinl, and promotes Beclinl interaction with STING, the key regulator for antiviral IFN signaling. Finally, knockdown of Beclinl partially reverses PLP2-TM＇s inhibitory effect on innate immunity which resulting in decreased coronavirus replication. These results sug- gested that coronavirus papain-like protease induces incomplete autophagy by interacting with Beclinl, which in turn modulates coronavirus replication and antiviral innate immunity.
文摘Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and con. sidered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to that of its bacterial ancestor＇s, consists of a circular loop and contains significant number of unmethylated DNA as CpG islands. The innate immune system plays an important role in the mammalian immune response. Recent research has demonstrated that mitochondrial DNA （mtDNA） activates several innate immune path- ways involving TLR9, NLRP3 and STING signaling, which contributes to the signaling platforms and results in effector responses. In addition to facilitating antibac- terial immunity and regulating antiviral signaling, mounting evidence suggests that mtDNA contributes to inflammatory diseases following cellular damage and stress. Therefore, in addition to its well-appreciated roles in cellular metabolism and energy production, mtDNA appears to function as a key member in the innate immune system. Here, we highlight the emerging roles of mtDNA in innate immunity.
文摘STING(stimulator of interferon genes)是天然免疫信号通路中一种新发现的蛋白质,在防御病毒及胞内细菌感染、介导Ⅰ型IFN产生过程中发挥重要功能.来自病原体的B型DNA与5′-3p dsRNA暴露在宿主细胞中后被相应的模式识别受体识别,通过不同的通路传递信号给STING.STING随后通过相似的机制招募TBK1激活IRF3,诱导干扰素表达.对细菌中的环二核苷酸c-di-GMP和c-di-AMP,STING则可以直接作为模式识别受体引发Ⅰ型干扰素反应.此外STING还能激活STAT6诱导特异趋化因子产生,吸引各种免疫细胞抵抗病毒感染.本文通过对STING的发现、结构、定位、功能、机理以及调节机制进行综述,以期为揭示病毒逃逸天然免疫调节机制和抗病毒新型免疫调节剂提供新的思路.
基金co-supported by the National Natural Science Foundation of China (Nos. 51622501 and 51621064)the high-level personnel innovation support program of Dalian (No. 2017RJ04)
文摘In wind tunnels, long cantilever sting support systems with low structural damping encounter flow separation and turbulence during wind tunnel tests, which results in destructive low-frequency and big-amplitude resonance, leading to data quality degradation and test envelope limitation. To ensure planed test envelope and obtain high-quality data, an active damping vibration control system independent of balance signal based on stackable piezoelectric actuators and velocity feedback using accelerometer, is proposed to improve the support stability and wind tunnel testing safety in transonic wind tunnel. Meanwhile, a design of powerful sting-root embedded active damping device is given and an active vibration control method is presented based on the mechanism analysis of aircraft model vibration. Furthermore, a self-adaptive fuzzy Proportion Differentiation(PD) control model is proposed to realize control parameters adjustment automatically for various testing conditions. Besides, verification tests are performed in laboratory and a continuous transonic wind tunnel. Experimental results indicate that the aircraft model does not vibrate obviously from -4° to 11° at Ma = 0.6, the number of useable angle-of-attack has increased by 7° at Ma = 0.6 and 5° at Ma = 0.7 respectively, satisfying the requirements of practical wind tunnel tests.
基金supported by the Natural Science Foundation of Zhejiang Province(LY23C190002)National Natural Science Foundation of China(32173004)Natural Science Foundation of Ningbo City(202003N4011)。
文摘The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway,comprised of cyclic GMP-AMP synthase(cGAS),stimulator of interferon genes(STING), and downstream signaling adaptors, plays an essential role in protective immune defense against microbial DNA and internal damaged-associated DNA and is responsible for various immune-related diseases.After binding with DNA, cytosolic cGAS undergoes conformational change and DNA-linked liquid-liquid phase separation to produce 2’3’-c GAMP for the activation of endoplasmic reticulum(ER)-localized STING. However, further studies revealed that cGAS is predominantly expressed in the nucleus and strictly tethered to chromatin to prevent binding with nuclear DNA, and functions differently from cytosoliclocalized cGAS. Detailed delineation of this pathway,including its structure, signaling, and regulatory mechanisms, is of great significance to fully understand the diversity of cGAS-STING activation and signaling and will be of benefit for the treatment of inflammatory diseases and cancer. Here, we review recent progress on the above-mentioned perspectives of the cGAS-STING signaling pathway and discuss new avenues for further study.
文摘We reported a case of multiple organ dysfunction syndrome （MODS） following about 300 wasp stings. The diagnosis was based on autopsy findings of acute pulmonary edema, acute kidney injury, hepatic and cardiac dysfunction, and cerebral edema. MODS is a life-threatening complication, and should be considered a possibility after multiple wasp stings. Our autopsy helped to establish the cause of unexpected death due to wasp stings and to elucidate a possible mechanism of MODS.
基金The following funding supports are acknowledged:NIH(R35 CA232109,PO1 DK094779,U19 AI067798,R01 AI141333,and R01 AI029564).
文摘Immunometabolism,which is the metabolic reprogramming of anaerobic glycolysis,oxidative phosphorylation,and metabolite synthesis upon immune cell activation,has gained importance as a regulator of the homeostasis,activation,proliferation,and differentiation of innate and adaptive immune cell subsets that function as key factors in immunity.Metabolic changes in epithelial and other stromal cells in response to different stimulatory signals are also crucial in infection,inflammation,cancer,autoimmune diseases,and metabolic disorders.The crosstalk between the PI3K-AKT-mTOR and LKB1-AMPK signaling pathways is critical for modulating both immune and nonimmune cell metabolism.The bidirectional interaction between immune cells and metabolism is a topic of intense study.Toll-like receptors(TLRs),cytokine receptors,and T and B cell receptors have been shown to activate multiple downstream metabolic pathways.However,how intracellular innate immune sensors/receptors intersect with metabolic pathways is less well understood.The goal of this review is to examine the link between immunometabolism and the functions of several intracellular innate immune sensors or receptors,such as nucleotide-binding and leucine-rich repeat-containing receptors(NLRs,or NOD-like receptors),absent in melanoma 2(AIM2)-like receptors(ALRs),and the cyclic dinucleotide receptor stimulator of interferon genes(STING).We will focus on recent advances and describe the impact of these intracellular innate immune receptors on multiple metabolic pathways.Whenever appropriate,this review will provide a brief contextual connection to pathogenic infections,autoimmune diseases,cancers,metabolic disorders,and/or inflammatory bowel diseases.
基金This work was supported by grants from the National Natural Science Foundation of China(C31872731,C32070910,C31470839)Zhengyi Scholar Foundation of School of Basic Medical Sciences,Fudan University(S25-01).
文摘The covalently closed circular DNA(cccDNA)of HBV plays a crucial role in viral persistence and is also a risk factor for developing HBV-induced diseases,including liver fibrosis.Stimulator of interferon genes(STING),a master regulator of DNA-mediated innate immune activation,is a potential therapeutic target for viral infection and virus-related diseases.In this study,agonist-induced STING signaling activation in macrophages was revealed to inhibit cccDNA-mediated transcription and HBV replication via epigenetic modification in hepatocytes.Notably,STING activation could efficiently attenuate the severity of liver injury and fibrosis in a chronic recombinant cccDNA(rcccDNA)mouse model,which is a proven suitable research platform for HBV-induced fibrosis.Mechanistically,STING-activated autophagic flux could suppress macrophage inflammasome activation,leading to the amelioration of liver injury and HBV-induced fibrosis.Overall,the activation of STING signaling could inhibit HBV replication through epigenetic suppression of cccDNA and alleviate HBV-induced liver fibrosis through the suppression of macrophage inflammasome activation by activating autophagic flux in a chronic HBV mouse model.This study suggests that targeting the STING signaling pathway may be an important therapeutic strategy to protect against persistent HBV replication and HBV-induced fibrosis.
文摘Cellular sensing of virus-derived nucleic acids is essential for early defenses against virus infections. In recent years, the discovery of DNA sensing proteins, including cyclic GMP-AMP synthase （cGAS） and gamma-interferon- inducible protein （IFI16）, has led to understanding of how cells evoke strong innate immune responses against incoming pathogens carrying DNA genomes. The signaling stimulated by DNA sensors depends on the adaptor protein STING （stimulator of interferon genes）, to enable expression of antiviral proteins, including type I interferon. To facilitate efficient infections, viruses have evolved a wide range of evasion strategies, targeting host DNA sensors, adaptor proteins and transcription factors. In this review, the current literature on virus-induced activation of the STING pathway is presented and we discuss recently identified viral evasion mechanisms targeting different steps in this antiviral pathway.
基金supported by the Grant Agreement(No.4.628.21.0004)with the Ministry of Education and Science of the Russian Federation(project unique identifier RFMEFI62815X0004)on the theme‘‘Development and implementation of the optimization of the aircraft power plant aerodynamics as a part of a 3rd generation multidisciplinary optimization and its application to optimization of promising new types of aircraft”
文摘A modern transonic computational fluid dynamics test case is described in this paper,which is the Aerodynamic Validation Model（AVM） from the Chinese Aeronautical Establishment（CAE）. The CAE-AVM is a representation of a modern transonic business jet aircraft with a design Mach number of 0.85. Numerical simulations for the AVM are conducted for two geometries： one baseline geometry, and one geometry that includes the applied model support system of the wind tunnel as well as the deformed wing shape that occurred during wind tunnel testing. The combined influence of wing deformation and model support interference on local and integral aerodynamic features is presented. Comparisons between CFD and experimental results are made; reasons of discrepancy between results from considered cases are analyzed.
基金This work was supported by the National Natural Science Foundation Regional Innovation and Development(No.U19A2003)National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09733001)+1 种基金Excellent Youth Foundation of the Sichuan Scientific Committee Grant in China(No.2019JDJQ008)Development Program of China(No.2016YFA0201402).
文摘Exposure to ionizing radiation,a physical treatment that inactivates live tumor cells,has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human clinical trials.However,the mechanisms by which irradiated cells function as immunogenic tumor vaccines and induce effective antitumor responses have not been fully explored.Here,we demonstrate that oxidized mitochondrial DNA(mtDNA)and stimulator of interferon genes(STING)signaling play a key roles in the enhanced antitumor effect achieved with an irradiated tumor cell vaccine.Elevations in ROS and oxidized mtDNA 8-OHG content could be induced in irradiated tumor cells.Oxidized mtDNA derived from irradiated tumor cells gained access to the cytosol of dendritic cells(DCs).Oxidized mtDNA,as a DAMP or adjuvant,activated the STING-TBK1-IRF3-IFN-β pathway in DCs,which subsequently cross-presented irradiated tumor cell-derived antigens to CD8^(+)T cells and elicited antitumor immunity.The results of our study provide insight into the mechanism by which an irradiated cell vaccine mediates antitumor immunity,which may have implications for new strategies to improve the efficacy of irradiated vaccines.
基金supported by National Natural Science Foundation of China(Nos.91853109,81730100,81872877,and 81673436)Mountain-Climbing Talents Project of Nanjing University(China)。
文摘Colorectal cancer(CRC), a malignant tumor worldwide consists of microsatellite instability(MSI) and stable(MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing wasperformed to explore the role of SHP2 in all cell types of tumor microenvironment(TME) from murine MC38 xenografts. Intratumoral cells were found to be functionally heterogeneous and responded significantly to SHP099, a SHP2 allosteric inhibitor. The malignant evolution of tumor cells was remarkably arrested by SHP099. Mechanistically, STING-TBK1-IRF3-mediated type I interferon signaling was highly activated by SHP099 in infiltrated myeloid cells. Notably, CRC patients with MSS phenotype exhibited greater macrophage infiltration and more potent SHP2 phosphorylation in CD68;macrophages than MSI-high phenotypes, suggesting the potential role of macrophagic SHP2 in TME. Collectively,our data reveals a mechanism of innate immunosuppression mediated by SHP2, suggesting that SHP2 is a promising target for colon cancer immunotherapy.
